The goal of this proposal is to develop a novel approach using Prostate Specific Membrane Antigen (PSMA)- directed radiotherapy as an immunogenic stimulus in combination with the immune checkpoint inhibitor pembrolizumab to provide durable tumor regressions in patients with PSMA-avid metastatic prostate cancer. This will be accomplished by using 68Ga-PSMA-11 PET to select patients for treatment, as well as utilizing robust immunologic assays developed in Dr. Lawrence Fong's laboratory at UCSF to quantify the magnitude and breadth of immunogenic stimulus provided by Lu-PSMA radioligand priming. The majority of metastatic CRPC tumors are avid for PSMA expression, and small molecule-based radioligand therapies targeting PSMA have demonstrated impressive response rates in heavily pre-treated patients. However, response durations are quite limited in duration. This is attributable to acquired radioresistance, progression of non-PSMA avid tumors, and cumulative toxicity limiting dose intensity. To overcome these limitations, we aim to shift the paradigm of PSMA-directed radiotherapy, utilizing a single dose of 177Lu-PSMA- 617 to achieve an initial tumor response and immunogenic priming, sustained by subsequent treatment with immune checkpoint inhibition. We hypothesize that a priming dose of 177Lu-PSMA-617 will result in rapid tumor response in PSMA-avid lesions that will induce antigen spread and host anti-tumor response that will be sustained with long-term immune checkpoint inhibition, leading to durable tumor regressions in both PSMA-avid and-negative prostate tumors. Our grant leverages the growing body of literature supporting radiation as an immunogenic priming stimulus, via induction of tumor infiltrating lymphocytes and expansion of T cell clonotypes, supporting the feasibility of this approach. To accomplish this important project, we have assembled an exceptional team of investigators with complimentary expertise in early phase drug development/clinical cancer research (Dr. Aggarwal), PSMA imaging and radioligand therapy (Dr. Hope), prostate cancer immunology and biology (Dr. Fong), and histopathology (Dr. Vandeneberg). In the current proposal, we aim to: Determine the recommended phase 2 dose and preliminary efficacy of 177Lu-PSMA-617 in combination with pembrolizumab in patients with PSMA-avid metastatic prostate cancer (Aim 1); Quantify the immunogenic priming effect of Lu-PSMA RLT (Aim 2). Successful results of our novel proof-of-concept study will form the strong justification for the subsequent evaluation of the combination in a randomized clinical trial, and ultimately may form the basis for a new treatment to improve disease outcomes for men with advanced prostate cancer.